Abstract

Background Most colon cancers start with dysregulated Wnt/β-catenin signalling and remain a major therapeutic challenge. Examining whether
HAMLET (human α-lactalbumin made lethal to tumour cells) may be used for colon cancer treatment is logical, based on the properties
of the complex and its biological context.

Objective To investigate if HAMLET can be used for colon cancer treatment and prevention. ApcMin/+ mice, which carry mutations relevant to hereditary and sporadic human colorectal tumours, were used as a model for human
disease.

Results Peroral HAMLET administration reduced tumour progression and mortality in ApcMin/+ mice. HAMLET accumulated specifically in tumour tissue, reduced β-catenin and related tumour markers. Gene expression analysis
detected inhibition of Wnt signalling and a shift to a more differentiated phenotype. In colon cancer cells with APC mutations, HAMLET altered β-catenin integrity and localisation through an ion channel-dependent pathway, defining a new mechanism
for controlling β-catenin signalling. Remarkably, supplying HAMLET to the drinking water from the time of weaning also significantly
prevented tumour development.

Conclusions These data identify HAMLET as a new, peroral agent for colon cancer prevention and treatment, especially needed in people
carrying APC mutations, where colon cancer remains a leading cause of death.